The immune response to antigen is characterized by an initial activation followed by the development of effector mechanisms, such as the delayed type hypersensitivity (DTH) and the secretion of specific antibody. Two distinct subsets of T helper (Th) cells, in murine and human systems, can be distinguished on the basis of lymphokine secretion. Thl cells secrete IL-2, IFN-y and lymphotoxi and provide help for the DTH response whereas Th2 cells secrete IL-4,IL-5, IL-6, and IL-1O and provide help for antigen specific antibody responses. These cells arise from a common precursor, the naive Th cell. This cell first differentiates into a Th0 cell which secretes large amounts of IL-2, and small amounts of both IL-4 and IFN- gamma. Several factors determine whether the Th0 will differentiate into either Thl or Th2 and these include the cytokine milieu, the antigen presenting cell and the density of antigenic peptide. It is of interest to better understand the regulation of the differentiation process as several diseases are associated with one response or the other; AIDs with Th2 responses and diabetes with Th1 responses. The specific aims of this proposal are to continue our work on the cross regulation of Th1 and Th2 cells by using the mathematical tools of dynamic modeling to study the differentiation of Th1 and Th2 cells from their common precursor. A model will be developed on the basis of the available data and the parameters included in the model will be estimated from a series of in vitro experiments that mimic the differentiation process. Other parameters, particularly those concerning Th0 cells, will be determined by a series of computer simulations. Finally, the model will be used to predict and suggest new experiments that will further our understanding of Th1/Th2 differentiation and that will suggest strategies for the manipulation of these responses. This approach could ultimately lead to possible immunotherapeutic manipulation in diseases characterized by an imbalance between these two important T helper cell subsets.